Process For Preparing Aminopyrimidine Derivatives

ABSTRACT

The present invention provides an improved process for preparing an aminopyrimidine derivative or pharmaceutically acceptable salt thereof having a selective inhibitory activity against protein kinases, especially against the protein kinases for mutant epidermal growth factor receptors. Additionally, the present invention provides novel intermediates useful for said process and processes for preparing the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 17/704,718, filedMar. 25, 2022, which is a continuation of U.S. Ser. No. 17/115,037,filed Dec. 8, 2020 (now U.S. Pat. No. 11,286,253, issued Mar. 29, 2022),which is a continuation of U.S. Ser. No. 16/633,684, filed Jan. 24, 2020(now U.S. Pat. No. 10,889,578, issued Jan. 12, 2021), which is theNational Stage of International Patent Application No. PCT/KR2018/008379filed Jul. 25, 2018, which claims the benefit of Korean applicationnumber 10-2017-0096212, filed Jul. 28, 2017, the entire contents of eachof which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to an improved process for preparing anaminopyrimidine derivative or pharmaceutically acceptable salt thereof.And also, the present invention relates to novel intermediates usefulfor said process and processes for preparing the same.

BACKGROUND ART

WO 2016/060443 has disclosed an aminopyrimidine derivative orpharmaceutically acceptable salt thereof having a selective inhibitoryactivity against protein kinases, especially against the protein kinasesfor mutant epidermal growth factor receptors. Said aminopyrimidinederivative or pharmaceutically acceptable salt thereof can provide aneffective and safe therapy against non-small cell lung cancers. WO2016/060443 has disclosed, as an aminopyrimidine derivative, for exampleN-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide of the following Formula 1 and aprocess for preparing the same.

WO 2016/060443 has also disclosed a process for preparing theaminopyrimidine derivative of Formula (I), for example a processaccording to the following Reaction Scheme. In the following ReactionScheme, R₁ may be methoxy, R₂ may be hydrogen, R₃ may be morpholinyl, R₄may be hydrogen, R₅ may be phenyl, R₆ may be hydrogen, and R₇ may bedimethylamino.

Specifically, the process for preparing the compound of Formula (I)according to the above Reaction Scheme comprises reacting a compound ofFormula (a) with a compound of Formula (b) by use of sodium hydride toobtain a compound of Formula (c); reacting the compound of Formula (c)with a compound of Formula (d) by use of sodium hydride to obtain acompound of Formula (e); performing reductive amination of the compoundof Formula (e) to obtain a compound of Formula (f); reducing thecompound of Formula (f) by use of iron and ammonium chloride to obtain acompound of Formula (g); and reacting the compound of Formula (g) withacryloyl chloride to obtain a compound of Formula (I).

Said process includes the reactions using sodium hydride, in order toprepare the compound of Formula (c) and the compound of Formula (e).However, since sodium hydride has a high possibility of fire andexplosion, there is a problem that it is difficult to use in industrialmass production.

And also, said process includes the use of iron in the step for reducingthe nitro group of the compound of Formula (f) to the amino groupthereof. However, the use of iron may cause corrosion and contaminationin a reactor, which makes it difficult to be applied to mass production.Further, during the reduction using iron and ammonium chloride to obtainthe compound of the Formula (g), unknown tars and degradation productsare produced; and the product (i.e., the compound of the Formula (g)) isobtained in black color. Therefore, in order to obtain the finalproduct, the compound of formula (I), having a suitable purity, it isrequired to perform the purification process by column chromatographywhich is difficult to apply to mass production. In addition, the yieldof the step for preparing the compound of Formula (g) is only about 60%.

In addition, since acryloyl chloride used in the final step forpreparing the compound of Formula (I) has low stability, it is difficultto handle at the production site. And also, since various degradationproducts are produced during the reaction of the compound of formula (g)with acryloyl chloride, it is difficult to prepare the compound ofFormula (I) having a suitable purity.

DISCLOSURE Technical Problem

The present invention provides an improved process which is suitable forindustrial mass production and which is able to produceN-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (the compound of Formula 1) or apharmaceutically acceptable salt thereof with high purity and yield.

And also, the present invention provides novel intermediates useful forsaid process and processes for preparing the same.

Technical Solution

According to an aspect of the present invention, there is provided aprocess for preparing

N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (the compound of formula 1) or apharmaceutically acceptable salt thereof, the process comprising (a)reactingN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(the compound of Formula 3) with a compound of Formula 4 to obtain acompound of Formula 2; and (b) reacting the compound of Formula 2 with abase to obtainN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide:

wherein, X is halogen.

In an embodiment, theN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(the compound of Formula 3) used in Step (a) may be obtained by aprocess comprising (i) reacting4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (the compound of Formula 6) with tinchloride in the presence of hydrochloric acid to obtain a complex ofFormula 5 and (ii) reacting the complex of Formula 5 with a base toobtainN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine:

In another embodiment, the4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (the compound of Formula 6) used in Step(i) may be obtained by reacting1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 7) with dimethylamine or a salt thereof.

In still another embodiment, the1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 7) may be obtained by reacting4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (thecompound of Formula 9) with 3-phenyl-1H-pyrazole-4-carbaldehyde (thecompound of Formula 10). The4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (thecompound of Formula 9) may be obtained by reactingN-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (the compound ofFormula 11) with 4-chloro-2-(methylsulfonyl)pyrimidine (the compound ofFormula 12). And also, theN-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (the compound ofFormula 11) may be obtained by performing a formylation of2-methoxy-4-morpholino-5-nitroaniline (the compound of Formula 13). The4-chloro-2-(methylsulfonyl)pyrimidine (the compound of Formula 12) maybe obtained by performing an oxidation of4-chloro-2-(methylthio)pyrimidine (the compound of Formula 18). The2-methoxy-4-morpholino-5-nitroaniline (the compound of Formula 13) maybe obtained by reacting 4-fluoro-2-methoxy-5-nitroaniline (the compoundof Formula 14) with morpholine (the compound of Formula 15).

In still another embodiment, the1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 7) may be obtained by reactingN-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (the compound ofFormula 11) with1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 16). The1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 16) may be obtained by reacting1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 17) with an oxidizing agent. The1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 17) may be obtained by reacting4-chloro-2-(methylthio)pyrimidine (the compound of Formula 18) with3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of Formula 10).

According to another aspect of the present invention, there is provideda compound of Formula 2 or salt thereof:

wherein, X is halogen.

According to still another aspect of the present invention, there isprovided a complex of Formula 5:

According to still another aspect of the present invention, there isprovided1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 16).

According to still another aspect of the present invention, there isprovided1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 17).

Advantageous Effects

The process of the present invention avoids the use of acryloyl chloridein the step for convertingN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(the compound of Formula 3, i.e., corresponding to the compound ofFormula (g) in WO 2016/060443) toN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (the compound of Formula 1, i.e.,corresponding to the compound of Formula (I) in WO 2016/060443). Thatis, the process of the present invention includes reacting the compoundof Formula 3 with 3-halogenopropionyl chloride to obtain a compound ofFormula 2 (which is a novel intermediate) and reacting the compound ofFormula 2 with a base to obtain the compound of Formula 1, the processof which minimizes the production of degradation products, thereby beingable to prepare the compound of Formula 1 in high purity and yield.

And also, the improved process of the present invention may avoid theuse of iron and ammonium chloride in the step for converting4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (the compound of Formula 6, i.e.,corresponding to the compound of Formula (f) in WO 2016/060443) toN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(the compound of Formula 3, i.e., corresponding to the compound ofFormula (g) in WO 2016/060443). That is, the process of the presentinvention includes reacting the compound of Formula 6 with tin chloridein the presence of an acid to obtain a complex of the compound ofFormula 6 and tin chloride; and reacting the complex with a base toobtain the compound of Formula 3, the process of which makes it possibleto prepare the compound of Formula 3 in high yield (e.g., 75% or more)and in high purity. And also, said process is able to solve the problemsof corrosion and contamination in a reactor which is caused by the useof iron. In addition, said process can avoid the production of unknowntars and degradation products; and therefore avoid performing thepurification process by column chromatography unsuitable for industrialmass production

In addition, the improved process of the present invention is able toexclude the use of sodium hydride having a high possibility of fire andexplosion in the steps for preparing the key intermediates, i.e.,4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (thecompound of Formula 9, i.e., corresponding to the compound of Formula(c) in WO 2016/060443) and1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 7, i.e., corresponding to the compound ofFormula (e) in WO 2016/060443). Therefore, the process of the presentinvention is suitable for industrial mass production.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides an improved process for preparingN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide or a pharmaceutically acceptablesalt thereof. The overall reaction schemes of the process of the presentinvention are represented as the following Reaction Scheme 1 or 2.

Hereinafter, the process of the present invention will be described indetail with reference to the respective steps of the Reaction Schemes 1and 2.

The present invention provides a process for preparingN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide (the compound of formula 1) or apharmaceutically acceptable salt thereof, the process comprising (a)reactingN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(the compound of Formula 3) with a compound of Formula 4 to obtain acompound of Formula 2; and (b) reacting the compound of Formula 2 with abase to obtainN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide:

wherein, X is halogen.

In the process of the present invention, X is preferably chlorine orbromine.

In the process of the present invention, the reacting of Step (a) may becarried out in the presence of one or more base(s) selected from thegroup consisting of potassium tert-butoxide, sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium phosphate (includingpotassium phosphate monobasic, potassium phosphate dibasic, andpotassium phosphate tribasic), sodium phosphate (including sodiumphosphate monobasic, sodium phosphate dibasic, and sodium phosphatetribasic), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), pyridine, triethylamine, diisopropylamine anddiisopropylethylamine. Preferably, the base may be sodium bicarbonate.The base may be used in an amount ranging from 1.0 to 5.0 equivalents,preferably from 1.0 to 3.0 equivalents, per 1 equivalent of the compoundof Formula 3. The reacting of Step (a) may be carried out in thepresence of a solvent selected from the group consisting ofacetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone,dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide,dimethyl sulfoxide, tetrahydrofuran, C₁˜C₅ alcohol, toluene, ethylacetate, isopropyl acetate, diethyl ether, water and a mixture thereof.Preferably, the solvent may be selected from the group consisting ofacetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone,dichloromethane, water and a mixture thereof. More preferably, thesolvent may be a mixed solvent of acetonitrile and water, a mixedsolvent of methyl ethyl ketone and water or a mixed solvent oftetrahydrofuran and water. The reaction of the compound of Formula 3with the compound of Formula 4 may be carried out at a temperatureranging from 0 to 50° C., preferably from 0 to 30° C. The compound ofFormula 2 may be isolated according to conventional methods, such asconcentration (e.g., concentration under reduced pressure etc.),filtration, drying, and so on.

The base used in Step (b) may be one or more selected from the groupconsisting of potassium tert-butoxide, sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium phosphate (includingpotassium phosphate monobasic, potassium phosphate dibasic, andpotassium phosphate tribasic), sodium phosphate (including sodiumphosphate monobasic, sodium phosphate dibasic, and sodium phosphatetribasic), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), pyridine, triethylamine, diisopropylamine anddiisopropylethylamine. Preferably, the base may be one or more selectedfrom the group consisting of sodium hydroxide, triethylamine anddiisopropylamine. More preferably, the base may be triethylamine. Thebase may be used in an amount ranging from 1.0 to 20.0 equivalents,preferably from 5.0 to 10.0 equivalents, per 1 equivalent of thecompound of Formula 2. The reacting of Step (b) may be carried out inthe presence of a solvent selected from the group consisting ofacetonitrile, methyl ethyl ketone, acetone, methyl isobutyl ketone,dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide,dimethyl sulfoxide, tetrahydrofuran, C₁˜C₅ alcohol, toluene, ethylacetate, isopropyl acetate, diethyl ether, water and a mixture thereof.Preferably, the solvent may be selected from the group consisting ofacetonitrile, tetrahydrofuran, methyl ethyl ketone, acetone,dichloromethane, water and a mixture thereof. More preferably, thesolvent may be a mixed solvent of acetonitrile and water, a mixedsolvent of methyl ethyl ketone and water or a mixed solvent oftetrahydrofuran and water. The reaction of the compound of Formula 2with the base may be carried out at a temperature ranging from 40 to150° C., preferably at a temperature ranging from 60 to 100° C., morepreferably at the reflux temperature of the used solvent. The compoundof Formula 1 prepared from said reaction may be isolated in the form offree base or in the form of organic or inorganic salt (for example, inthe form of mesylate salt) according to conventional methods.

In an embodiment of the process of the present invention, Step (a) andStep (b) may be carried out in a one-pot reaction, without isolating thecompound of Formula 2. Therefore, the process of the present inventionis suitable for industrial mass production.

In the process of the present invention, theN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(the compound of Formula 3) used in Step (a) may be obtained by aprocess comprising (i) reacting4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (the compound of Formula 6) with tinchloride in the presence of hydrochloric acid to obtain a complex ofFormula 5 and (ii) reacting the complex of Formula 5 with a base toobtainN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine:

In Step (i), said tin chloride may be used in the form of anhydrate orhydrate (e.g., dihydrate). The tin chloride may be used in an amountranging from 2.0 to 10.0 equivalents, preferably from 3.0 to 5.0equivalents, per 1 equivalent of the compound of Formula 6. The acid maybe used in an amount ranging from 2.0 to 10.0 equivalents per 1equivalent of the compound of Formula 6. And also, the reacting of Step(i) may be carried out at a temperature ranging from 0 to 100° C.,preferably from 40 to 85° C. Therefore, the reaction may be carried outunder a mild condition, and thus is suitable for industrial massproduction. The reaction may be carried out in the presence of one ormore solvent(s) selected from the group consisting of water, C₁˜C₁₀alcohol (for example, methanol, ethanol, propanol, isopropanol, butanol,and so on), dichloromethane, tetrahydrofuran, acetonitrile and ethylacetate. In an embodiment, the solvent may be ethanol or a mixed solventof ethanol and dichloromethane. The complex of Formula 5 produced fromStep (i) may be subject to the subsequent step [i.e., Step (ii)],without the isolation thereof. And also, the complex of Formula 5produced from Step (i) may be isolated from the reaction mixture per seor isolated by crystallization with an antisolvent. The antisolvent maybe one or more selected from the group consisting of dichloromethane,ethyl acetate, C₁˜C₅ alcohol (for example, methanol, ethanol,isopropanol, butanol, and so on), acetone, acetonitrile, methyl ethylketone, tetrahydrofuran, hexamethylphosphoramide, dimethyl ether,diethyl ether, diisopropyl ether, ethyl acetate, dimethoxyethane andtoluene. Preferably, the antisolvent may be dichloromethane. Althoughthe amount of the antisolvent to be used is not particularly limited,the antisolvent may be used in a weight ratio ranging from 2 to 20times, preferably from 3 to 10 times, based on the complex of Formula 5.The crystallization may be also carried out at a temperature rangingfrom 0 to 40° C., preferably from 0 to 25° C.

Step (ii) provides theN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(the compound of Formula 3) through reacting the complex of Formula 5with a base. The base may be one or more selected from the groupconsisting of sodium hydroxide, potassium hydroxide, sodium carbonate,sodium bicarbonate, potassium carbonate, potassium phosphate (includingpotassium phosphate monobasic, potassium phosphate dibasic, andpotassium phosphate tribasic), and sodium phosphate (including sodiumphosphate monobasic, sodium phosphate dibasic and sodium phosphatetribasic). Preferably, the base may be sodium hydroxide.

In the process of the present invention, the4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (the compound of Formula 6) used in Step(i) may be obtained by reacting1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 7) with dimethylamine or a salt thereof. Thereacting may be carried out in the presence of one or more reducingagent(s) selected from the group consisting of sodiumtriacetoxyborohydride, sodium cyanoborohydride and sodium borohydride,preferably the presence of sodium triacetoxyborohydride. The reducingagent may be used in an amount ranging from 1.0 to 5.0 equivalents,preferably from 1.0 to 2.0 equivalents, per 1 equivalent of the compoundof Formula 7, although the amount thereof may vary according to thereducing agents. The reacting may be carried out in the presence of oneor more base(s) selected from the group consisting ofdiisopropylethylamine and triethylamine. And also, the reacting may becarried out in the presence of one or more solvent(s) selected from thegroup consisting of C₁˜C₁₀ alcohol (for example, methanol, ethanol,propanol, isopropanol, butanol, and so on), dimethylacetamide,dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile andethyl acetate. The reacting may be carried out at a temperature rangingfrom 0 to 50° C., preferably from 20 to 30° C. Therefore, the reactionmay be carried out under a mild condition, and thus is suitable forindustrial mass production. The compound of Formula 6 produced from saidreaction may be isolated from the reaction mixture per se or isolated bycrystallization with an antisolvent. The antisolvent may be C₁˜C₅alcohol (for example, methanol, ethanol, isopropanol, butanol, and soon), water, or a mixture thereof, preferably water. Although the amountof the antisolvent to be used is not particularly limited, theantisolvent may be used in a weight ratio ranging from 2 to 20 times,preferably from 3 to 10 times, based on the complex of Formula 7. Thecrystallization may be also carried out at a temperature ranging from 0to 40° C., preferably from 20 to 30° C.

In an embodiment, the1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 7) may be obtained by reacting4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (thecompound of Formula 9) with 3-phenyl-1H-pyrazole-4-carbaldehyde (thecompound of Formula 10) (see Reaction Scheme 1). The reaction of thecompound of Formula 9 with the compound of Formula 10 may be carried outin the presence of one or more base(s) selected from the groupconsisting of potassium tert-butoxide, sodium hydroxide, potassiumhydroxide, sodium hydride, sodium carbonate, potassium carbonate,potassium phosphate (including potassium phosphate monobasic, potassiumphosphate dibasic, and potassium phosphate tribasic), sodium phosphate(including sodium phosphate monobasic, sodium phosphate dibasic, andsodium phosphate tribasic), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), pyridine, triethylamine, diisopropylamine anddiisopropylethylamine. Preferably, the base may be one or more selectedfrom the group consisting of sodium carbonate, potassium carbonate, andpotassium phosphate. And also, the reaction may be carried out in thepresence of one or more solvent(s) selected from the group consisting ofdichloromethane, dichloroethane, dimethylformamide, dimethylacetamide,dimethyl sulfoxide, tetrahydrofuran, C₁˜C₅ alcohol, ethyl acetate,acetone, methyl ethyl ketone, acetonitrile and toluene. Preferably, thesolvent may be selected from the group consisting of dichloromethane,dimethylformamide and dimethylacetamide. More preferably, the solventmay be dimethylformamide. And also, the reaction may be carried out at atemperature ranging from 0 to 100° C., preferably from 40 to 60° C.

In the process of the present invention, the4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (thecompound of Formula 9) may be obtained by reactingN-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (the compound ofFormula 11) with 4-chloro-2-(methylsulfonyl)pyrimidine (the compound ofFormula 12) (see Reaction Scheme 1). The reaction of the compound ofFormula 11 with the compound of Formula 12 may be carried out in thepresence of one or more base(s) selected from the group consisting ofsodium C₁˜C₆ alkoxide, potassium C₁˜C₆ alkoxide, sodium carbonate,potassium carbonate, lithium carbonate, cesium carbonate, sodiumbicarbonate, potassium bicarbonate, potassium phosphate,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine,dimethylaminopyridine and triethylamine. Preferably, the base may besodium C₁˜C₆ alkoxide or potassium C₁˜C₆ alkoxide. And also, thereaction may be carried out in the presence of an inert solvent, forexample in the presence of one or more solvent(s) selected from thegroup consisting of dimethylformamide, dimethylacetamide,dichloromethane, dimethyl sulfoxide, tetrahydrofuran,hexamethylphosphoramide, C₁˜C₅ alcohol, diethyl ether, ethyl acetate,acetonitrile and acetone. Preferably, the solvent may bedimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixturethereof. And also, the reaction may be carried out at a temperatureranging from 0 to 50° C., preferably from 0 to 10° C.

In the process of the present invention, theN-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (the compound ofFormula 11) may be obtained by performing a formylation of2-methoxy-4-morpholino-5-nitroaniline (the compound of Formula 13) (seeReaction Scheme 1). The formylation may be carried out with a mixture ofacetic acid (e.g., anhydrous acetic acid) and formic acid. Each amountof acetic acid and formic acid to be used may range from 2 to 5 moles,preferably from 2.5 to 3.5 moles, per 1 mole of the compound of Formula13. And also, the formylation may be carried out in the presence of aninert solvent, for example in the presence of one or more solvent(s)selected from the group consisting of dimethylformamide,dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran,hexamethylphosphoramide, C₁˜C₅ alcohol, diethyl ether, ethyl acetate,acetonitrile and acetone. Preferably, the solvent may bedimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixturethereof. And also, the reaction may be carried out at a temperatureranging from 0 to 70° C., preferably from 20 to 50° C.

In the process of the present invention, the4-chloro-2-(methylsulfonyl)pyrimidine (the compound of Formula 12) maybe obtained by performing an oxidation of4-chloro-2-(methylthio)pyrimidine (the compound of Formula 18). Theoxidation may be carried out with one or more oxidizing agent(s)selected from the group consisting of potassium permanganate, chromicacid, oxygen, hydrogen peroxide and 3-chloroperbenzoic acid. Preferably,the oxidizing agent may be hydrogen peroxide. The amount of theoxidizing agent to be used may range from 1.8 to 10.0 moles, preferablyfrom 2.0 to 5.0 moles, per 1 mole of the compound of Formula 18. Andalso, the reaction rate can be increased by performing the oxidation inthe presence of a catalyst such as ammonium molybdate tetrahydrate. Inaddition, the reaction may be carried out in the presence of one or moresolvent(s) selected from the group consisting of C₁˜C₅ alcohol, carbontetrachloride, chloroform, dichloromethane, acetone, methyl ethylketone, methyl isobutyl ketone, cyclohexanone, pentane, hexane, heptane,octane, nonane, decane, undecane, dodecane, cyclohexane, petroleumether, kerosene, toluene, xylene, mesitylene and benzene. Preferably,the solvent may be C₁˜C₅ alcohol.

In the process of the present invention, the2-methoxy-4-morpholino-5-nitroaniline (the compound of Formula 13) maybe obtained by reacting 4-fluoro-2-methoxy-5-nitroaniline (the compoundof Formula 14) with morpholine (the compound of Formula 15). Thereaction may be carried out in the presence of one or more base(s)selected from the group consisting of sodium C₁˜C₆ alkoxide, potassiumC₁˜C₆ alkoxide, sodium carbonate, potassium carbonate, lithiumcarbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate,potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), pyridine, dimethylaminopyridine, triethylamine anddiisopropylethylamine. Preferably, the base may be triethylamine ordiisopropylethylamine. The reaction may be carried out in the presenceof an inert solvent, for example in the presence of one or moresolvent(s) selected from the group consisting of dimethylformamide,dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran,hexamethylphosphoramide, C₁˜C₅ alcohol, diethyl ether, ethyl acetate,acetonitrile and acetone. Preferably, the solvent may be selected fromthe group consisting of acetonitrile, dimethylformamide anddimethylacetamide. And also, the reaction may be carried out at atemperature ranging from 0 to 100° C., preferably from 70 to 80° C.

In another embodiment, the1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 7) may be obtained by reactingN-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (the compound ofFormula 11) with1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 16) (see Reaction Scheme 2). The reaction ofthe compound of Formula 11 with the compound of Formula 16 may becarried out in the presence of one or more base(s) selected from thegroup consisting of sodium C₁˜C₆ alkoxide, potassium C₁˜C₆ alkoxide,sodium carbonate, potassium carbonate, lithium carbonate, cesiumcarbonate, sodium bicarbonate, potassium bicarbonate, potassiumphosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), pyridine, dimethylaminopyridine, and triethylamine. Preferably,the base may be one or more selected from the group consisting of sodiumC₁˜C₆ alkoxide, potassium C₁˜C₆ alkoxide, sodium carbonate, potassiumcarbonate, and potassium phosphate. If the compound of Formula 7 isprepared according to the Reaction Scheme 2, it is possible to avoid theuse of sodium hydride. And also, the reaction may be carried out in thepresence of an inert solvent, for example in the presence of one or moresolvent(s) selected from the group consisting of dimethylformamide,dimethylacetamide, dichloromethane, dimethyl sulfoxide, tetrahydrofuran,hexamethylphosphoramide, C₁˜C₅ alcohol, diethyl ether, ethyl acetate,acetonitrile and acetone. Preferably, the solvent may bedimethylformamide, dimethylacetamide, tetrahydrofuran, or a mixturethereof. And also, the reaction may be carried out at a temperatureranging from 0 to 50° C., preferably from 0 to 10° C.

In the process of the present invention, the1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 16) may be obtained by reacting1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 17) with an oxidizing agent (see ReactionScheme 2). The oxidation may be carried out with one or more oxidizingagent(s) selected from the group consisting of potassium permanganate,chromic acid, oxygen, hydrogen peroxide and 3-chloroperbenzoic acid.Preferably, the oxidizing agent may be hydrogen peroxide. The amount ofthe oxidizing agent to be used may range from 1.8 to 10.0 moles,preferably from 2.0 to 5.0 moles, per 1 mole of the compound of Formula17. And also, the reaction rate can be increased by performing theoxidation in the presence of a catalyst such as ammonium molybdatetetrahydrate. In addition, the reaction may be carried out in thepresence of one or more solvent(s) selected from the group consisting ofC₁˜C₅ alcohol, carbon tetrachloride, chloroform, dichloromethane,acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone,pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane,cyclohexane, petroleum ether, kerosene, toluene, xylene, mesitylene andbenzene.

In the process of the present invention, the1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 17) may be obtained by reacting4-chloro-2-(methylthio)pyrimidine (the compound of Formula 18) with3-phenyl-1H-pyrazole-4-carbaldehyde (the compound of Formula 10). Thereaction of the compound of Formula 18 with the compound of Formula 10may be carried out in the presence of one or more base(s) selected fromthe group consisting of potassium tert-butoxide, sodium hydroxide,potassium hydroxide, sodium hydride, sodium carbonate, potassiumcarbonate, potassium phosphate (including potassium phosphate monobasic,potassium phosphate dibasic, and potassium phosphate tribasic), sodiumphosphate (including sodium phosphate monobasic, sodium phosphatedibasic, and sodium phosphate tribasic),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine,triethylamine, diisopropylamine and diisopropylethylamine. Preferably,the base may be selected from the group consisting of sodium carbonate,potassium carbonate, and potassium phosphate. The reaction may becarried out in the presence of one or more solvent(s) selected from thegroup consisting of dichloromethane, dichloroethane, dimethylformamide,dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C₁˜C₅ alcohol,ethyl acetate, acetone, methyl ethyl ketone, acetonitrile and toluene.Preferably, the solvent may be selected from the group consisting ofdichloromethane, dimethylformamide and dimethylacetamide. Morepreferably, the solvent may be dimethylformamide. And also, the reactionmay be carried out at a temperature ranging from 0 to 100° C.,preferably from 40 to 60° C.

The present invention includes, within its scope, novel intermediatesuseful for said improved processes.

That is, the present invention provides a compound of Formula 2 or saltthereof:

wherein, X is halogen.

And also, the present invention provides a complex of Formula 5:

And also, the present invention provides1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 16).

And also, the present invention provides1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(the compound of Formula 17).

The following examples are provided for illustration purposes only, andare not intended to limit the scope of the invention.

Example 1. Preparation of 2-methoxy-4-morpholino-5-nitroaniline(Compound 13)

A mixture of 4-fluoro-2-methoxy-5-nitroaniline (60.0 g, 0.322 mol),acetonitrile (600.0 mL), diisopropylethylamine (83.3 g, 0.645 mol), andmorpholine (84.2 g, 0.967 mol) was refluxed under stirring for 4 hours.To the reaction mixture, was purified water (1.8 L) added. The resultingsolid was filtered and then dried in vacuo to obtain 78.0 g of thetitled compound. (Yield: 95.5%)

¹H-NMR (400 MHz, DMSO) δ 7.21 (s, 1H), 6.76 (s, 1H), 5.03 (s, 2H), 3.89(s, 3H), 3.69 (t, 4H), 2.92 (t, 4H)

Example 2. Preparation ofN-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (Compound 11)

A mixture of anhydrous acetic acid (254.0 g, 2.487 mol) and formic acid(137.4 g, 2.984 mol) was stirred at 50° C. for 30 minutes.2-Methoxy-4-morpholino-5-nitroaniline (210.0 g, 0.829 mol) andtetrahydrofuran (219.0 mL) were added to the reaction mixture, which wasthen stirred at 20-25° C. for 1 hour. To the reaction mixture, wasmethyl tert-butyl ether (2.1 L) added. The resulting solid was filteredand then dried in vacuo to obtain 211.0 g of the titled compound.(Yield: 90.5%)

¹H-NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.85 (s, 1H), 8.29 (d, 1H), 6.83(s, 1H), 3.99 (s, 1H), 3.72-3.74 (t, 4H), 3.03-3.05 (t, 4H)

Example 3. Preparation of 4-chloro-2-(methylsulfonyl)pyrimidine(Compound 12)

A 35% hydrogen peroxide solution (90.7 g, 0.933 mol) and ammoniummolybdate tetrahydrate (11.5 g, 0.01 mol) were added to a solution of4-chloro-2-(methylthio)pyrimidine (50.0 g, 0.311 mol) in ethanol (250.0mL). The reaction mixture was stirred for 2 hours and then extractedwith dichloromethane (200.0 mL) and purified water (250.0 mL). Theseparated organic layer was washed with a 10% sodium sulfite solutionand purified water and then concentrated under reduced pressure. Theresulting residue was crystallized by adding isopropyl alcohol thereto.The resulting solid was filtered and then dried in vacuo to obtain 51.2g of the titled compound. (Yield: 85.4%)

¹H-NMR (400 MHz, DMSO) δ 9.05 (d, 1H), 8.06 (d, 1H), 3.42 (s, 3H)

Example 4. Preparation of4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine(Compound 9)

A mixture of N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (15.0 g,0.05 mol), tetrahydrofuran (40.0 mL), and dimethylacetamide (60.0 mL)was cooled to 0-5° C. Sodium tert-butoxide (5.6 g, 0.06 mol) and4-chloro-2-(methylsulfonyl)pyrimidine (11.3 g, 0.06 mol) were added tothe mixture, which was then stirred at 0-10° C. for 1 hour. A 2N NaOHsolution (75.0 mL) was added to the reaction mixture. The reactionmixture was stirred at room temperature for 1 hour and then purifiedwater (150.0 mL) was added thereto. The resulting solid was filtered andthen dried in vacuo to obtain 16.1 g of the titled compound. (Yield:82.6%)

¹H-NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.38-8.40 (t, 2H), 6.95 (d, 1H),6.83 (s, 1H), 6.95 (d, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.73-3.75 (t,4H), 3.06-3.08 (t, 4H)

Example 5. Preparation of1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(Compound 17)

A mixture of 4-chloro-2-(methylthio)pyrimidine (102.6 g, 0.639 mol),3-phenyl-1H-pyrazole-4-carbaldehyde (100.0 g, 0.581 mol), potassiumcarbonate (160.5 g, 1.162 mol), and dimethylformamide (700.0 mL) wasstirred at 40-50° C. for 2 hours. Purified water (1.6 L) was slowlyadded to the reaction mixture, which was then stirred at roomtemperature for 2 hours. The resulting solid was filtered and then driedin vacuo to obtain 154.0 g of the titled compound. (Yield: 81.4%)

¹H-NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 9.20 (s, 1H), 8.65 (d, 1H),7.84-7.86 (m, 2H), 7.67-7.71 (m, 3H), 2.65 (s, 3H)

Example 6. Preparation of1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(Compound 16)

A 35% hydrogen peroxide solution (3.4 g, 30.3 mmol) and ammoniummolybdate tetrahydrate (0.4 g, 0.3 mmol) were added to a solution of1-(2-(methylthio)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(3.0 g, 10.1 mmol) in ethanol (21.0 mL). The reaction mixture wasstirred for 2 hours and then extracted with dichloromethane (30.0 mL)and purified water (30.0 mL). The separated organic layer was washedwith a 10% sodium sulfite solution (21.0 mL) and purified water and thenconcentrated under reduced pressure. The resulting residue wascrystallized by adding isopropyl alcohol thereto. The resulting solidwas filtered and then dried in vacuo to obtain 2.8 g of the titledcompound. (Yield: 84.3%)

¹H-NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 9.30 (s, 1H), 9.00 (d, 1H),8.27 (d, 2H), 7.87-7.93 (m, 2H), 7.48-7.54 (m, 3H), 3.44 (s, 3H)

Example 7. Preparation of

1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(Compound 7)

A mixture of4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (3.2g, 0.009 mol), dimethylformamide (22.4 mL), potassium carbonate (2.4 g,0.017 mol), and 3-phenyl-1H-pyrazole-4-carbaldehyde (1.7 g, 0.010 mol)was stirred at 40-50° C. for 12 hours. To the reaction mixture, waspurified water (32.0 mL) added. The resulting solid was filtered andthen dried in vacuo to obtain 4.3 g of the titled compound. (Yield:98.0%)

¹H-NMR (400 MHz, DMSO) 8.94 (s, 1H), 8.38 (d, 1H), 8.38 (s, 1H), 6.96(d, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.73-3.75 (t, 4H), 3.06-3.09 (t,4H)

Example 8. Preparation of1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(Compound 7)

A mixture of N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide (0.4 g,1.4 mmol), tetrahydrofuran (2.6 mL), dimethylacetamide (1.8 mL) andsodium tert-butoxide (0.2 g, 2.0 mmol) was stirred at 10° C. for 2hours. After the temperature of the reaction mixture was adjusted toroom temperature,1-(2-(methylsulfonyl)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(0.5 g, 1.5 mmol) was added thereto. The reaction mixture was stirred atroom temperature for 1 hour. A 2N NaOH solution (2.1 mL) was added tothe reaction mixture, which was then stirred for about 1 hour. Theresulting solid was filtered and then dried in vacuo to obtain 0.67 g ofthe titled compound. (Yield: 93.9%)

¹H-NMR (400 MHz, DMSO) 8.94 (s, 1H), 8.38 (d, 1H), 8.38 (s, 1H), 6.96(d, 1H), 6.83 (s, 1H), 3.94 (s, 3H), 3.73-3.75 (t, 4H), 3.06-3.09 (t,4H)

Example 9. Preparation of4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine(Compound 6)

Dimethylamine hydrochloride (39.0 g, 0.479 mol) and triethylamine (161.4g, 1.595 mol) were added to a solution of1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde(160.0 g, 0.319 mol) in dimethylformamide (1,120 mL). The reactionmixture was stirred at room temperature for 30 minutes. Sodiumtriacetoxyborohydride (121.7 g, 0.574 mol) was added to the reactionmixture, which was then stirred at room temperature for 3 hours.Purified water (2,240 mL) was added to the reaction mixture, which wasthen stirred for 1 hour. The resulting solid was filtered under reducedpressure and then dried in vacuo to obtain 164.0 g of the titledcompound. (Yield: 96.9%)

¹H-NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.57-8.61 (q, 3H), 7.98 (d, 2H),7.52 (d, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 6.88 (s, 1H), 4.01 (s, 3H),3.75-3.77 (t, 4H), 3.41 (s, 2H), 3.07-3.10 (t, 4H), 2.24 (s, 6H)

Example 10. Preparation ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine tin complex (Compound 5)

A mixture of4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (10 g, 0.019 mol), tin chloride dihydrate(21.3 g, 0.094 mol), ethanol (200.0 mL), and a 35% hydrochloric acidsolution (13.1 mL, 0.151 mol) was refluxed under stirring for 2 hours.The reaction mixture was cooled to 20-30° C. Dichloromethane (100.0 mL)was slowly added to the reaction mixture, which was then stirred for 2hours. The resulting solid was filtered under reduced pressure and thendried in vacuo to obtain 21.6 g of the titled compound.

¹H-NMR (400 MHz, DMSO) δ 10.07 (br, 1H), 10.01 (br, 1H), 9.24 (s, 1H),8.62-8.63 (d, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.73-7.74 (d, 2H),7.51-7.58 (m, 3H), 7.39-7.40 (d, 1H), 7.13 (s, 1H), 4.54 (s, 2H), 3.92(s, 3H), 3.81 (s, 4H), 2.91 (s, 4H), 2.70 (s, 6H)

Example 11. Preparation ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine tin complex (Compound 5)

A mixture of4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine (20 g, 0.038 mol), ethanol (400.0 mL),dichloromethane (200.0 mL), and a 35% hydrochloric acid solution (26.2mL, 0.302 mol) was stirred for 30 minutes. Tin chloride dihydrate (42.5g, 0.189 mol) was added to the reaction mixture, which was then refluxedunder stirring for 2 hours. The reaction mixture was cooled to roomtemperature and then stirred for 2 hours. The resulting solid wasfiltered under reduced pressure and then dried in vacuo to obtain 40.6 gof the titled compound. (Content Yield: 82.1%)

¹H-NMR (400 MHz, DMSO) δ 10.07 (br, 1H), 10.01 (br, 1H), 9.24 (s, 1H),8.62-8.63 (d, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.73-7.74 (d, 2H),7.51-7.58 (m, 3H), 7.39-7.40 (d, 1H), 7.13 (s, 1H), 4.54 (s, 2H), 3.92(s, 3H), 3.81 (s, 4H), 2.91 (s, 4H), 2.70 (s, 6H)

Example 12. Preparation ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine (Compound 3)

A mixture ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diaminetin complex (40.6 g), dichloromethane (200.0 mL), and a 2N NaOH solution(200.0 mL) was stirred at room temperature for 1 hour and then filtered.After the resulting filtrate was left standing, the separated organiclayer was treated with activated carbon and then concentrated underreduced pressure. Ethanol (100.0 mL) was added to the mixture, which wasthen stirred. The resulting solid was filtered and then dried in vacuoto obtain 14.2 g of the titled compound. (Yield: 75.2%)

¹H-NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 8.48 (d, 1H), 8.16 (s, 1H), 7.95(d, 2H), 7.41-7.49 (m, 4H), 7.28 (s, 1H), 6.72 (s, 1H), 4.53 (s, 2H),3.75-3.77 (t, 7H), 3.42 (s, 2H), 2.83 (t, 3H), 2.22 (s, 6H)

Example 13. Preparation of3-chloro-N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)propanamide(Compound 2, X=Cl)

3-Chloropropionyl chloride (0.16 g, 1.30 mmol) was added to a mixture ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(0.5 g, 0.99 mmol), sodium bicarbonate (0.25 g, 2.99 mmol), andacetonitrile (5.0 mL). The reaction mixture was stirred at 20-30° C. for3 hours. Purified water (5.0 mL) was added to the reaction mixture,which was stirred for 1 hour and then filtered under reduced pressure.The resulting solid was dried in vacuo to obtain 0.50 g of the titledcompound. (Yield: 85.0%)

¹H-NMR (400 MHz, DMSO) δ 9.09 (s, 1H), 9.06 (s, 1H), 8.79 (s, 1H),8.50-8.51 (d, 1H), 8.17 (s, 1H), 8.02 (d, 2H), 7.45-7.48 (t, 2H),7.39-7.42 (t, 1H), 7.31 (d, 1H), 6.89 (s, 1H), 3.98-3.99 (t, 2H), 3.88(s, 3H), 3.78-3.80 (t, 4H), 3.43 (s, 2H), 2.85-2.86 (t, 4H), 2.21 (s,6H)

Example 14. Preparation of3-bromo-N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)propanamide(Compound 2, X=Br)

3-Bromopropionyl chloride (0.13 mL, 1.297 mmol) was slowly added to amixture ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(0.5 g, 0.998 mmol), sodium bicarbonate (0.25 g, 3.00 mmol), andacetonitrile (5.0 mL). The reaction mixture was stirred at 20-30° C. for3 hours. Purified water (5.0 mL) was added to the reaction mixture,which was stirred for 1 hour and then filtered under reduced pressure.The resulting solid was dried in vacuo to obtain 0.52 g of the titledcompound. (Yield: 81.9%)

¹H-NMR (400 MHz, DMSO) δ 9.08 (s, 2H), 8.80 (s, 1H), 8.50 (d, 1H), 8.16(s, 1H), 8.02 (d, 2H), 7.45-7.48 (t, 2H), 7.39-7.42 (t, 1H), 7.31 (s,1H), 3.88 (s, 3H), 3.83-3.85 (t, 2H), 3.79-3.81 (t, 4H), 3.43 (s, 2H),3.09-3.12 (t, 2H), 2.85-2.87 (t, 4H), 2.19 (s, 6H)

Example 15. Preparation ofN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide(Compound 1)

A mixture of3-bromo-N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)propanamide(10.0 g, 16.9 mmol), acetonitrile (200.0 mL), and triethylamine (17.1 g,169.2 mmol) was refluxed under stirring for 16 hours. The reactionmixture was cooled to 20-30° C. and then concentrated under reducedpressure to remove the solvent. Dichloromethane (100.0 mL) and purifiedwater (100.0 mL) were added to the reaction mixture, which was thenstirred. The separated organic layer was concentrated under reducedpressure and then n-propanol (200.0 mL) was added thereto, followed byrefluxing under stirring. The reaction mixture was slowly cooled to20-30° C. and then stirred for 2 hours. The resulting solid was filteredunder reduced pressure and then dried in vacuo to obtain 8.0 g of thetitled compound. (Yield: 85.0%)

¹H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H),8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m, 2H), 7.34-7.36 (m, 1H),7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H),5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s,4H), 2.21 (s, 6H)

Example 16. Preparation ofN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide(Compound 1)

3-Chloropropionyl chloride (0.3 g, 2.60 mmol) was added to a mixture ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(1.0 g, 1.99 mmol), acetonitrile (20.0 mL), and sodium bicarbonate (0.5g, 5.99 mmol). The reaction mixture was stirred at 20-30° C. for 2hours. Triethylamine (2.0 g, 19.9 mmol) was added to the reactionmixture, which was then refluxed under stirring for 16 hours. Thereaction mixture was cooled to 20-30° C. and then concentrated underreduced pressure to remove the solvent. Dichloromethane (15.0 mL) andpurified water (10.0 mL) were added to the reaction mixture, which wasthen stirred. The separated organic layer was concentrated under reducedpressure and then n-propanol (20.0 mL) was added thereto, followed byrefluxing under stirring. The reaction mixture was slowly cooled to20-30° C. and then stirred for 2 hours. The resulting solid was filteredunder reduced pressure and then dried in vacuo to obtain 0.83 g of thetitled compound. (Yield: 75.0%)

¹H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H),8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m, 2H), 7.34-7.36 (m, 1H),7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H),5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s,4H), 2.21 (s, 6H)

Example 17. Preparation ofN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide(Compound 1)

3-Chloropropionyl chloride (0.3 g, 2.60 mmol) was added to a mixture ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(1.0 g, 1.99 mmol), tetrahydrofuran (17.0 mL), purified water (1.7 mL),and sodium bicarbonate (1.1 g, 5.99 mmol). The reaction mixture wasstirred at 20-30° C. for 2 hours. Triethylamine (2.0 g, 19.9 mmol) wasadded to the reaction mixture, which was then refluxed under stirringfor 16 hours. The reaction mixture was cooled to 20-30° C. and thenconcentrated under reduced pressure to remove the solvent.Dichloromethane (10.0 mL) and purified water (10.0 mL) were added to thereaction mixture, which was then stirred. The separated organic layerwas concentrated under reduced pressure and then n-propanol (20.0 mL)was added thereto, followed by refluxing under stirring. The reactionmixture was slowly cooled to 20-30° C. and then stirred for 2 hours. Theresulting solid was filtered under reduced pressure and then dried invacuo to obtain 0.88 g of the titled compound. (Yield: 79.5%)

¹H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H),8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m, 2H), 7.34-7.36 (m, 1H),7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H),5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s,4H), 2.21 (s, 6H)

Example 18. Preparation ofN-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide(Compound 1)

3-Chloropropionyl chloride (6.6 g, 0.052 mol) was added to a mixture ofN1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine(20.0 g, 0.039 mol), methyl ethyl ketone (160.0 mL), and sodiumbicarbonate (10.1 g, 0.120 mol). The reaction mixture was stirred at20-30° C. for 2 hours. Dichloromethane (10.0 mL) and purified water(10.0 mL) were added to the reaction mixture, which was then stirred.The separated organic layer was concentrated under reduced pressure andthen methyl ethyl ketone (300.0 mL) and triethylamine (40.4 g, 0.400mol) were added thereto, followed by refluxing under stirring for 10hours. The reaction mixture was cooled to 0-5° C. and then stirred for 2hours. The resulting solid was filtered under reduced pressure and thendried in vacuo to obtain 17.7 g of the titled compound. (Yield: 79.9%)

¹H-NMR (400 MHz, DMSO) δ 9.15 (s, 2H), 9.08 (s, 1H), 8.53-8.55 (d, 1H),8.18 (s, 1H), 8.04-8.06 (d, 2H), 7.47-7.50 (m, 2H), 7.34-7.36 (m, 1H),7.34 (d, 1H), 6.96 (s, 1H), 6.71-6.78 (q, 1H), 6.43-6.44 (d, 1H),5.84-5.85 (d, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.46 (1s, 1H), 2.86 (s,4H), 2.21 (s, 6H).

What is claimed:
 1. A compound of Formula (III)

or a salt thereof.